The compound Triazole, having the following chemical formula (II):
has the chemical name 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine and CAS RN 486460-21-3.
Triazole is a key intermediate for the synthesis of Sitagliptin of formula (I):
a substance also known as MK-0431 and having chemical name 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine. Sitagliptin is commercially available as the phosphate salt monohydrate under the trade name Januvia.
This active pharmaceutical ingredient is an oral antihyperglycemic (antidiabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor. This enzyme-inhibiting drug is used alone or in combination with other oral antihyperglycemic agents, such as for example metformin or a thiazolidinedione, for treatment of diabetes mellitus type 2. The benefit of this medicine is its fewer side effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values.
A synthetic process for the preparation of Sitagliptin is carried out by means of various steps, in particular one of them is the process for the preparation of Triazole.
A few methods for the preparation of Triazole have been disclosed.
In particular, Organic Letters, 7 (6), 1039-1042, 2005 discloses the synthesis of [1,2,4]Triazolo[4,3-r]piperazines via condensation of high reactive chloromethyloxadiazoles with ethylenediamins. The above mentioned article describes the preparation of different products, such as Oxadiazole, Triazole and substituted Triazoles. In particular, scheme 3, that is present in said article at page 1040, shows and briefly illustrates the preparation of Triazole 1a, starting from oxadiazole 3a proceeding to amidine 4a, thus to obtain 1a, through reflux of 4a in methanol. The experimental details, related to the preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo [4,3-a]pyrazine hydrochloride salt 1a, are not described in the same article, but they are disclosed in supporting information for [1,2,4]Triazolo[4,3-r]piperazines via condensation of high reactive chloromethyloxadiazoles at page 4.
Specifically, WO2004/080958 discloses, in example 1, in particular Step D, the preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo [4,3-a]pyrazine, hydrochloride salt (1-4), that was carried out by means of several steps with different solvents, and mostly with a substantial large amount of volumes, about 15 volumes.
In the above mentioned preparation, a warmed suspension of amidine in methanol (4V) was reacted with aqueous hydrochloric acid (37% HCl, 0.4V), producing a seed bed formed after the cooling. Later starting from the beforehand produced mixture, MTBE (11V) was added. The resulting slurry was cooled and filtered. Finally, for obtaining triazole 1-4, the solid cake was washed with ethanol:MTBE (1:3) solution (2V) and dried under vacuum at 45° C. In this method the conversion of amidine to triazole is carried out in methanol and water, while the isolation of the product is carried out from a mixture of methanol, water and MTBE.
The prior art methods this suffers of the drawbacks that the productivity of triazole is relatively low, especially considering the large volumes of solvents used, thus effecting the overall production capacity. Moreover, considering large productions, the recovery of the solvents is quite complex and require long cycling time.